9-alpha-substituted estratrienes as selectively active estrogens

a technology of estratrienes and estratrienes, which is applied in the direction of steroid, medical preparations, organic chemistry, etc., can solve the problems of increasing the risk of endometrial carcinoma, ineffective substance types, and numerous risks and side effects of exogenous gonadotropin treatmen

Inactive Publication Date: 2008-08-19
BAYER INTELLECTUAL PROPERTY GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because of the stimulating action of the estrogens that are used on the endometrium, which results in an increase of the risk of endometrial carcinoma (Harlap, S.
In this case, these are partial agonists of estrogen receptor subtype “ERα.” This substance type is ineffective, however, with respect to the therapy of acute postmenopausal symptoms, such as, e.g., hot flashes.
In many respects, the treatment with exogenic gonadotropins is accompanied by numerous risks and side effects.
The greatest risk consists in an overstimulation of the ovaries, which in severe cases can represent a serious danger to life (OHSS=Ovarian Hyperstimulation Syndrome).
Other side effects are the high costs of the in-vitro fertility treatment that must be paid by the coupled.

Method used

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  • 9-alpha-substituted estratrienes as selectively active estrogens
  • 9-alpha-substituted estratrienes as selectively active estrogens
  • 9-alpha-substituted estratrienes as selectively active estrogens

Examples

Experimental program
Comparison scheme
Effect test

example 2

9α-Vinyl-18a-homo-estra-1,3,5(10)-triene-3,16α-diol

Stage 1

3,16α-Bis[(perhydropyran-2-yl)oxy]-18a-homo-estra-1,3,5(10)-triene-9-carbonitrile

[0187]1.03 g (2.26 mmol) of 3,16α-bis[(perhydropyran-2-yl)oxy]-18a-homo-estra-1,3,5(10)-triene, 48.2 mg (0.45 mmol) of lithium perchlorate and 0.71 ml (5.66 mmol) of trimethylsilyl cyanide and introduced into 10 ml of methylene chloride (molecular sieve) and cooled under inert gas to about −70° C. while being stirred. Then, 0.77 g (3.39 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, dissolved in 65 ml of methylene chloride, is added in drops within 1 hours. After about 1 hour (heating to room temperature), the reaction solution is mixed with sodium bicarbonate solution, and the reaction products are extracted with methylene chloride. The crude product that is obtained by concentration by evaporation of the organic phases is purified by chromatography. After chromatography on silica gel (cyclohexane / ethyl acetate, 4 / 1), 0.74 g (68% of theory)...

example 3

9α-(2′,2′-Difluorovinyl)-estra-1,3,5(10)-triene-3,16α-diol

Stage 1

3,16α-Bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrile

[0194]Reaction of 3,16α-bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene analogously to Example 1, stage 1 yields 3,16α-bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrile.

[0195]Yield: 58% of theory

Stage 2

3,16α-Dihydroxy-estra-1,3,5(10)-triene-9-carbaldehyde

[0196]Reaction of 3,16α-bis[(perhydropyran-2-yl)oxy]-estra-1,3,5(10)-triene-9-carbonitrile analogously to Example 1, stage 2 yields 3,16α-dihydroxy-estra-1,3,5(10)-triene-9-carbaldehyde;

[0197]Yield: 83% of theory

Stage 3

9α-(2,2-Difluorovinyl)-estra-1,3,5(10)-triene-3,16α-diol

[0198]1.5 ml of dimethoxyethane (molecular sieve), 0.3 ml of pentane and 0.13 ml (0.77 mmol) of diethyl(difluoromethyl)-phosphonate are introduced into a reaction flask that was rendered inert, and cooled to about −75° C. After 0.72 ml (1.07 mmol) of tert-butyllithium (1.5 M in pentane) is added and after 30...

example 4

9α-(2′,2′-Difluorovinyl)-18a-homo-estra-1,3,5(10)-triene-3,16α-diol

Stage 1

3,16α-Bis[(perhydropyran-2-yl)oxy]-18a-homo-estra-1,3,5(10)-triene-9-carbonitrile

[0201]Reaction of 3,16α-bis[(perhydropyran-2-yl)oxy]-18a-homo-estra-1,3,5(10)-triene analogously to Example 1, stage 1 yields 3,16α-bis[(perhydropyran-2-yl)oxy]-18a-homoestra-1,3,5(10)-triene-9-carbonitrile.

[0202]Yield: 58% of theory.

Stage 2

3,16α-Dihydroxy-18a-homo-estra-1,3,5(10)-triene-9-carbaldehyde

[0203]Reaction of 3,16α-bis[(perhydropyran-2-yl)oxy]-18a-homo-estra-1,3,5(10)-triene-9-carbonitrile analogously to Example 1, stage 2 yields 3,16α-dihydroxy-18a-homo-estra-1,3,5(10)-triene-9-carbaldehyde.

[0204]Yield: 87% of theory

Stage 3

9α-(2,2-Difluorovinyl)-18a-homo-estra-1,3,5(10)-triene-3,16α-diol

[0205]Reaction of 3,16α-dihydroxy-18a-homo-estra-1,3,5(10)-triene-9-carbaldehyde; Reaction conditions and execution of the reaction as well as molar ratios as in the 3rd stage of 9α-(2,2-difluorovinyl)-estra-1,3,5(10)-triene-3,16α-diol.

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Abstract

This invention describes the new 9α-substituted estratrienes of general formula Iin which R3, R7, R7′, R13, R16 as well as R17 and R17′ have the meanings that are indicated in the description and R9 means a straight-chain or branched-chain, optionally partially or completely halogenated alkenyl radical with 2 to 6 carbon atoms, an ethinyl or prop-1-inyl radical, as pharmaceutical active ingredients that exhibit in vitro a higher affinity to estrogen receptor preparations from rat prostates than to estrogen receptor preparations from rat uteri and in vivo preferably a preferential action on the ovary in comparison to the uterus, their production, their therapeutic use and pharmaceutical dispensing forms that contain the new compounds.The invention also describes the use of these compounds for treating estrogen-deficiency-induced diseases and conditions.

Description

FIELD OF THE INVENTION[0001]This invention relates to new compounds as pharmaceutical active ingredients, which have in vitro a higher affinity to estrogen receptor preparations from rat prostates than to estrogen receptor preparations from rat uteri and in vivo a preferential action in the ovary in comparison to the uterus, their production, their therapeutic use and pharmaceutical dispensing forms that contain the new compounds.[0002]The chemical compounds are new, steroidal, tissue-selective estrogens.BACKGROUND OF THE INVENTION[0003]The efficiency of estrogens in the treatment of hormone-deficiency-induced symptoms such as hot flashes, atrophy of estrogen target organs and incontinence, as well as the successful use of estrogen therapies for prevention of bone mass loss in peri- and postmenopausal women, is well documented and generally accepted (Grady et al. 1992, Ann Intern Med 117:1016-1037). It is also well documented that estrogen replacement therapy in postmenopausal women...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/56C07J1/00C07J41/00
CPCC07J41/00A61P15/02A61P15/08A61P17/06A61P19/02A61P19/08A61P25/28A61P5/24A61P9/00A61P9/12
Inventor KOSEMUND, DIRKMUELLER, GERDHILLISCH, ALEXANDERFRITZEMEIER, KARL-HEINRICHMUHN, PETER
Owner BAYER INTELLECTUAL PROPERTY GMBH
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